The present invention relates to a slow-release composite having encapsulated therein pyroglutamyl-histidyl-triptophyl-seryl-tyrosyl-D-leucyl-leucyl-arginyl-pro line ethylamide or a salt thereof, as well as a process for producing the same.
Pyroglutamyl-histidyl-triptophyl-seryl-tyrosyl-D-leucyl-leucyl-arginyl-prol ine ethylamide or salts thereof (an acetate salt will hereunder sometimes be referred to as TAP-144) were screened during studies on the synthesize LH-RH (luteinizing hormone-releasing hormone) derivatives. This ethylamide has a greater activity than naturally occurring LH-RH and is represented by the following formula: ##STR1## (an abbreviation authorized by IUPAC-IUB Commission on Biological Nomenclature). This compound can be converted to salts by reaction with suitable acids, such as hydrohalogenic acids (e.g. hydrochloric acid and hydrobromic acid), perchloric acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, lactic acid, pyroracemic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid and sulfanic acid. For the sake of convenience, the following description is limited to an acetate salt of the compound, or TAP-144.
When TAP-144 is repeatedly administered to male or female animals, their serum LH and FSH are reduced and the growth of their reproductive organs may sometimes be regulated. In female rats, TAP-144 exhibits the ability to regulate the growth of ovary and control breast cancer induced by 7,12-dimethylbenzene anthracene. Therefore, it is expected that TAP-144 has therapeutic effects on hormone-dependent human breast cancer. In male rats administered TAP-144, there occurs a significant decrease in the weight of the testicles, prostate glands and other secondary reproductive organs, as well as in the amount of serum testosterone. Furthermore, TAP-144 is capable of regulating the growth of tumors transplanted in the prostate glands of a male rat. Therefore, TAP-144 is also expected to have therapeutic effects on human prostatic cancer.
TAP-144 is water-soluble and remains stable in an aqueous solution for at least one year if it is held at room temperature. In order to maximize its pharmacological effects, TAP-144 is daily administered by subcutaneous injection but this may impose an excessive burden on patients.
The present inventors have made various efforts to develop a method of administering TAP-144 by which the pharmacological effects of TAP-144 are retained while imposing minimum burden on patients. As a result, the inventors have found that this object can be achieved by using a slow-release formulation wherein TAP-144 is encapsulated in a polymer matrix. The present invention has been accomplished on the basis of this finding.